DR VERMA: So there have been a lot of mechanisms and hypotheses that have been put forward, ranging from natriuresis to diuresis, which occur with these agents. There is the recent concept that there may be differential regulation of the intravascular and interstitial component, where SGLT-2 inhibitors may have greater reductions on interstitial vs intravascular volume. Then there has been the hypothesis that these agents may have a direct effect on the sodium hydrogen exchanger by inhibiting exchange—they may have effects to reduce intracellular cardiomyocyte sodium and calcium. There is the ketone hypothesis that by raising beta-hydroxybutyrate, they provide an alternative fuel source for the myocardium, and through that mechanism improve myocardial energetics potentially.
Then, of course, there is the hypothesis that these agents are primarily working at the level of the kidney, which I believe is probably the most cogent hypothesis in that they cause the hemodynamic effect at the level of the kidney, which explains the renal benefit through either tubuloglomerular feedback and afferent arteriole constriction. More importantly, that benefit appears to occur both in people with and without diabetes because in DAPA-HF, even in the nondiabetic population, the GFR decline ocurred similarly to what is seen in people with diabetes and that may trigger a reduction in efferent sympathetic activation. The kidneys are closely associated with central sympathetic activation, and through improving renal function and reducing renal stress, these agents may reduce sympathetic tone, and that may be one of the mechanisms. So, there have been many hypotheses and theories that have been put forward, but I think the bottom line is that the fact that they worked similarly in people with and without diabetes in DAPA-HF really suggests that glucose is off the table with respect to a key mechanism of HF and renal protection.
DR PUNZI: When you look at the clinical trials with diabetic hypertensive patients, microvascular disease seems to be significantly improved when compared with macrovascular disease. I think that relates back to what you were just saying. If you look at the HOPE trial17 with ramipril (2.5 mg, 10 mg, or placebo) given at bedtime, along with vitamin E, what they found in that clinical trial was that a significant benefit was derived in the diabetic patients (38% of patients). This is when clinicians started using renin-angiotensin system blockers in their diabetic cohort even though, when looking at the pathophysiology of diabetic hypertensive patients they are volume repleted, so they’re low-renin hypertensive patients. Numerous guidelines warrant the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in these patients.
I think we’re seeing a similar phenomenon now with the SGLT-2 inhibitors, specifically with dapagliflozin, that there is a possible mechanistic action that is very similar to these renin-angiotensin system blockers and that’s why we’re seeing significant benefit. I think, once again, that clinicians today don’t really think that the diabetic patient would be at risk for developing HF. Is there anything that we can do to shift that thinking, to make them more aware? The impetuous behind this thinking is that we now have treatment that is going to benefit these patients early on as well as long term. So, Dr McCullough, are there any closing comments that you want to make with regards to this or anything else that we left out?
DR MCCULLOUGH: I would conclude by saying that, in my view, we are in the middle of an HF and T2DM pandemic. I think the opportunity that you’ve outlined in terms of general risk factor control, of blood pressure reduction, and now treatment with SGLT-2 inhibitors has the potential to markedly reduce the burden of HF, which currently is the leading cause of nontraumatic adult hospitalization certainly in the United States. I think there is a bright future for this new class of antidiabetic agents and believe they will play a large role in the future treatment of patients with and without diabetes at risk for HF hospitalization and cardiovascular death.
DR PUNZI: Great, thank you, Dr McCullough. Would you like to summarize, Dr Verma?
DR VERMA: My comments are similar in that HF and renal disease remain recalcitrant problems in diabetes and we for many years have been, for lack of a better term, wondering why glucose-lowering strategies have not moved the needle.
So now we’ve generated the evidence to suggest that these agents have not just a significant but a profound effect on prevention and treatment of HF and an even bigger effect on prevention and treatment of renal disease. Therefore, we just need to overcome clinical inertia. We need to find a way to get past the fact that although the metformin and DPP-4 inhibitor combination is a safe and neutral combination, it doesn’t really change someone’s prognosis. So, if you are the gate keeper of your patients’ outcomes, then we need to remember that we have strategies that can actually prevent and treat these two important and interrelated complications. Clinical practice guidelines are really echoing the results of the trials in that regard.
DR PUNZI: Dr McCullough and Dr Verma, thank you. I think that we’ve tried to emphasize the point that we’ve got to start our treatment early. We can’t just start these diabetic individuals with medications where the only goal is to lower glucose (sulfonylureas are the most commonly prescribed drug in the United States for diabetes). With diabetes being a coronary heart disease equivalent, I think that the use of the SGLT-2 inhibitors should be utilized earlier in the algorithm. I think that, as Dr McCullough and Dr Verma well described, with dapagliflozin, not only do we help to lower blood sugar but also decrease BP and decrease the risk of HF hospitalizations. When utilizing dapagliflozin, the BP reduction is about 5 mm Hg. With a drop of 2 mm Hg in clinical trials there is a reduction of ischemic heart disease of 7%, stroke 10%, and then HF of about 15%. The key take-home message is to treat early and be very aggressive and assertive with your therapies. The SGLT-2 class has brought with it significant cardiovascular morbidity and mortality improvements in patients. Embracing these new therapies now will lead to significant cardiovascular benefits that these patients are going to have long term. With that we will conclude this roundtable. Thank you very much, gentlemen.
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